CZ20011886A3 - Azithromycin ethanolate, process of its preparation and pharmaceutical preparations containing thereof - Google Patents

Abstract

Crystalline azithromycin is disclosed, as well as a method for preparing it by the gradual crystallization from ethanol by the addition of a minimal amount of water to effect crystal formation. Pharmaceutical compositions containing this form of azithromycin are also disclosed. <IMAGE>

Description

Azithromycin ethanolate, preparation process and its pharmaceutical preparations

Technical field

The present invention relates to novel ethanolate of azithromycin, processes for its preparation and pharmaceutical preparations containing the novel ethanolate.

BACKGROUND OF THE INVENTION

Azithromycin, 9-deoxo-9α-aza-9α-methyl-9α-homoerythromycin A having the formula

is a semisynthetic macrolide antibiotic related to erythromycin A, which is useful in treating infections caused by susceptible organisms. The present invention provides a novel non-hygroscopic form of azithromycin, methods of preparation, and pharmaceutical compositions comprising the form.

Azithromycin can be prepared by the methods described in US Patent Nos. 4517359 and 4474768. According to European Patent Application EP 298650, azithromycin obtained by these methods is a hygroscopic monohydrate. Because of its hygroscopic nature, it is difficult to prepare and maintain this monohydrate in a form having a constant, reproducible water content, and is particularly difficult to handle during preparation. EP 298650 describes a dehydrated form of azithromycin which is less hygroscopic than the previously known monohydrate. The process described in EP 298650 for the formation of a dehydrated form is based on crystallization from tetrahydrofuran, hexane and water.

Chinese patent application CN 1093370 discloses an azithromycin crystal having a water content of 4-6%. This form of azithromycin is reported to be less hygroscopic than the dehydrate described in patent EP 298650. The method disclosed in patent CN 1093370 for the preparation of the disclosed form of azithromycin is based on crystallization from acetone and water.

Description of the invention

The present invention provides a novel azithromycin ethanolate which is less hygroscopic than azithromycin monohydrate. The new ethanolate has an ethanol content of from about 1.5% to about 3% and a water content of from about 2% to about 4%.

The present invention also provides a process for preparing azithromycin ethanolate comprising the steps of:

Dissolution of azithromycin in ethanol,

Adding water to the azithromycin solution so that crystallization of the azithromycin begins and a suspension is formed, and

Isolation of azithromycin crystals.

The present invention further provides a pharmaceutical composition comprising a therapeutic amount of azithromycin ethanolate in accordance with the present invention, and a pharmaceutically acceptable carrier.

Brief description of the pictures

Figure 1 is a comparison of the hygroscopicity of azithromycin ethanolate of the present invention and azithromycin monohydrate in the relative humidity range based on the data of EP 298650.

Figure 2 is a characteristic powder X-ray diffraction pattern of azithromycin ethanolate, which is the subject of the present invention.

Detailed description of the invention

The present invention describes a novel azithromycin ethanolate which has a content of 3% and a water content of from about 2% to about less than the previously used monohydrate of ethanol and is less hygroscopic to about 1.5 to about 1.5%.

4%. The ethanol content is between about 1.5% and about 2.5%. The water content is preferably between about 2.5% and about 3.5%. A comparison of the hygroscopicity of the ethanolate of the present invention and azithromycin monohydrate is shown in Figure 1.

The process of preparing azithromycin of the present invention utilizes for azithromycin than ethanol, ethanolate, which is the object that water is worse, so adding water to crystallize. For the solvent of the solution of the second azithromycin in ethanol, heating the solution of azithromycin in ethanol in the presence of water promotes crystallization.

In accordance with the process aspects of the present invention, azithromycin is dissolved in absolute ethanol of about 2.5: 1 (ethanol: azithromycin by weight) at a temperature of preferably from about 20 ° C to the invention in a ratio of between about 10 ° C and about 80 ° C , about 30 ° C. A minimum amount of water is added, i.e. an amount not exceeding 20% (by weight versus ethanol) of about 6, preferably a constant temperature of up to 16%. The solution is slowly heated in a gradient over a first period of preferably about 3 to 8 hours, reaching a maximum of about 2 to hours, a temperature of about 30 ° C to 80 ° C, and preferably about 40 ° C to about 60 ° C at the end of the first time interval. . Crystallization begins

in a temperature range of about 30-45 ° C. During the first time period, the water content of the solution is gradually increased, but only to a concentration not exceeding about 50%.

At the end of the first time interval, the resulting suspension is maintained at maximum temperature for a second time period of about 1 to about 18 hours, preferably about 1 to about 4 hours. During the second time interval, additional water is added to complete the crystallization process.

At the end of the second time interval, the suspension is cooled using a constant temperature gradient over a third time period of about 1 to about 18 hours, preferably about 2 to about 4 hours, reaching a final temperature of about 20 ° C. The resulting precipitate is collected by filtration and dried to constant weight. Table 1 shows the water content of the novel azithromycin ethanolate using Karl Fisher analysis and the ethanol content using gas chromatography.

Table 1. Ethanol and water content of azithromycin ethanolate

Batch Ethanol content (gas chromatography) Water content (Karl- Fisher) % w / w (w / w) % w / w AND 2.2 3.24 (B) 2.3 2.46 C 2.2 2.71 D 2.3 2.77 E 2.2 3.28 F 1.52 2.7 G 1.7 3.4

In accordance with the present invention, the novel azithromycin ethanolate can be prepared in the form of pharmaceutical preparations which are particularly useful for the treatment of infections caused by susceptible organisms. Such preparations include the novel ethanolate of azithromycin with pharmaceutically acceptable carriers and / or excipients.

For example, these preparations may be formulated as drugs for oral, parenteral, rectal, transdermal, buccal or nasal administration. Suitable forms for oral administration include tablets, compressed or coated tablets, dragees, powdered sachets for reconstitution, hard or gelatin capsules, sublingual tablets, syrups and suspensions. Suitable forms for parenteral administration include aqueous and non-aqueous solutions or emulsions, while suitable forms for rectal administration include suppositories with hydrophilic or hydrophobic vehicles. For topical applications, the invention provides ointments or aerosol preparations known in the art. Suitable aerosol systems known in the art are provided for nasal access.

Experimental details

Hygroscopicity profiles were obtained by keeping samples in controlled humidity chambers for 2 weeks followed by Karl Fisher water content analysis.

Gas chromatograms were obtained using a Hewlett-Packard 5890 gas chromatograph.

X-ray powder diffraction was performed using methods known in the art using a Phillips X-Ray, Goniometer model 1050/70 powder diffractometer at a scanning rate of 2 ° per minute with Cu radiation at a wavelength of λ = 1.5418 A.

The invention will be better understood from the following Examples. However, the examples are merely illustrative, not limiting. Those skilled in the art will readily appreciate specific methods, and the results discussed are purely illustrative of the invention, and are merely illustrative of the invention. As described in more detail in the claims that follow.

DETAILED DESCRIPTION OF THE INVENTION

Preparation of Azithromycin ethanolate

Ten grams of azithromycin was placed in a 0.25 liter, 3-neck, 3-necked, twin-shell jacket equipped with a mechanical stirrer, condenser and thermometer and containing 30 mL of 20 ° C absolute ethanol. Three ml of 20 ° C water was added to the solution at a constant temperature gradient until 55 ° C was reached after 4 hours. Between 35 ° C and 55 ° C, additional water was slowly added at regular time intervals ... to a total volume of 11 ml. After reaching a temperature of 55 ° C, the resulting suspension was maintained at this temperature for 2 hours, during which an additional 49 mL of water was added. The suspension was then cooled from 55 ° C to 20 ° C over 2 hours. The precipitate was filtered. After drying, 9 g of azithromycin ethanolate was obtained.

Although certain presently preferred embodiments of the invention have been described herein, it will be apparent to those skilled in the art to which modifications and modifications may be made without departing from the spirit and scope of the invention. For this reason, it is intended that the invention be limited only to the extent defined by the appended claims and the applicable rules of the law.

Claims (15)

PATENT CLAIMS An azithromycin ethanolate having an ethanol content of about 1.5% to about 3%. The ethanolate according to claim 1 having a water content of about 2% to 4%. The ethanolate according to claim 2, wherein the water content is between about 2.5% and about 3.5%. The ethanolate according to claim 1, wherein the ethanol content is about 1.5% to about 2.5%. The ethanolate of claim 4, wherein the water content is about 2% to about 4%. The ethanolate according to claim 5, wherein the water content is between about 1.5% and about 3.5%. 7. Azithromycin ethanolate, which is significantly characterized by X-ray powder diffraction as shown in Figure 2. A process for preparing azithromycin ethanolate 1 comprising the steps of: dissolving azithromycin in ethanol, Adding water to the azithromycin solution so that crystallization of the azithromycin begins and a suspension is formed, and Isolation of azithromycin crystals. The method of claim 9, further comprising the step of maintaining the suspension for a period of time at a temperature of about 30 ° C to about 80 ° C. The method of claim 9, wherein additional water is added to the suspension and the suspension is maintained at a temperature of about 30 ° C to about 80 ° C for about 1 to about 18 hours. The method of claim 10, wherein the suspension was cooled to a temperature of about 20 ° C prior to isolation of the azithromycin crystals. The method of claim 8, wherein the ethanolate has an ethanol content of from about 1.5% to about 3%. The method of claim 12, wherein the ethanolate has a water content of from about 2% to about 4%. The method of claim 8, wherein the ethanolate is significantly characterized by powder X-ray diffraction as shown in Figure 2. 15. A pharmaceutical composition comprising a therapeutically effective amount of the ethanolate of claim 1 and a pharmaceutically acceptable carrier.